Progressive atherosclerosis and restenosis following angioplasty are more common and occur at an earlier age in diabetic than in nondiabetic patients, and the consequences of atherosclerosis (stroke, coronary artery and peripheral vascular disease) are the primary causes of mortality in the diabetic population. The thrombospondins (TSPs) are a family of multifunctional proteins that interact with numerous matrix proteins and cell surface receptors. Only very limited information had linked the TSPs with diabetes and atherosclerosis. This has changed with the recent completion of a large scale genetic association study (GeneQuest) which found that single nucleotide polymorphisms (SNP) in TSP-1, TSP-2 and TSP-4 were not only associated with premature coronary artery disease, but were the only three of more than 80 SNP analyzed that were highly correlated with disease. These observations prompted us to assess the effects of high glucose on TSP release from vascular cells, and a significant increase was observed. Based upon these findings, we hypothesize that changes in TSP production by vascular cells exposed to high glucose may lead to the accelerated development of atherosclerotic lesions in diabetes. Now, by studying the functional differences between the variants, insights can be gained into the mechanisms by which the TSPs may induce atherosclerotic lesions in diabetes. Accordingly, the overall goal of this project is to elucidate the role of the TSPs in the accelerated development of atherosclerotic lesions in diabetes and to identify the molecular basis for the proatherogenic effects of the variant forms of TSP. The Specific Aims are: 1. To establish the mechanism by which glucose regulates TSP expression in vascular cells. 2. To characterize the expression of TSPs in the vascular wall, heart and brain of diabetic Zucker rats and to establish differences between diabetic and control Zucker rats in TSP expression patterns in response to vascular injury. 3. To identify the molecular mechanisms and the structural basis for the proatherogenic effects of the SNP in the coding regions of the TSPs. The mentored Research Scientist Development Award would greatly assist Dr. Olga I. Stenina in making a successful transition to an independent researcher in the field of diabetes and its cardiovascular complications.